This 12-month randomized double-blind placebo-controlled early Phase II study of older veterans with mild cognitive impairment (MCI) seeks to investigate the role of curcumin for the prevention of Alzheimer's Disease (AD). MCI often represents incipient AD, as underlying AD neuropathology is common in MCI. Over the first 6 months of the study, we will assess curcumin effects on blood-based biomarkers, brain glucose metabolism, and cognitive and functional parameters predictive of AD risk. Preclinical data suggest curcumin targets early and late steps in AD pathogenesis through its anti-oxidant, anti-inflammatory, and anti-tau/A aggregate activities. Prior studies of curcumin in AD were limited by poor uptake, but we will use a novel curcumin formulation to achieve previously established target free curcumin blood levels, facilitating delivery to the brain. Over the second 6 months of this study, we will assess the potential for synergism between curcumin treatment and aerobic exercise on our biomarker and clinical indices of AD risk. Exercise improves some aspects of cognition and increases IGF-1 and BDNF levels in the brain. These effects are likely to be potentiated by curcumin, which, in addition to its other effects, reduces insulin/neurotrophic factor resistance. General Design: We will examine the effects of 12 months of curcumin supplementation on a panel of plasma biomarkers identified in both the UCLA and ADNI MCI cohorts as indicative of AD risk. Plasma will be collected at 0, 6 and 12 months. Additional endpoints include neuropsychological, behavioral, and functional assessments at 0, 6 and 12 months and FDG-PET brain imaging at 0 and 6 months. Since physical activity levels may independently modulate rates of progression to AD, the second half of the trial will assess for potential additive benefits derived from an aerobi exercise enrichment program. We have chosen Yoga instead of typical treadmill exercise because it includes both resistance training and aerobic poses in specific sequences that may help sustain attention and reduce attrition. Standard Yoga sequences (Sun Salutations) are equivalent to moderate aerobic exercise, and Yoga studies have lower dropout rates than other comparable exercise trials. In the aerobic yoga class, by one month of training, instructors will increase intensity of practice to ensure target heart rates (60-80% of maximum heart rate) are met and subjects are sweating prior to beginning of cool-down sequence. The non-aerobic yoga group controls for potential confounds such as social interaction and active participation and may improve indices of quality of life and depression (compared to baseline), but is unlikely to provide sufficient exercise to improve biomarker or MCI-relevant clinical indices. Objectives: The specific aims are to determine the impact of 12 months of curcumin supplementation on potential plasma biomarkers of AD, brain glucose metabolism, and cognitive, behavioral, and functional endpoints in older veterans with MCI (Aim 1), and to determine whether the addition of an aerobic exercise program can further potentiate the effects of curcumin supplementation (Aim 2). Hypotheses: We hypothesize that curcumin supplementation will improve cerebral glucose metabolism at 6 months, modify blood-based biomarkers of AD risk at 6 and 12 months, and improve cognitive, behavioral, and functional endpoints at 12 months. We further hypothesize that more substantial biomarker and clinical improvements will be seen in the curcumin + aerobic Yoga treatment group relative to the other treatment groups. Potential Outcomes: This work will help evaluate impact of curcumin dosing on selective biomarker changes associated with conversion to AD to establish whether there is sufficient rationale for larger prevention trials (ADCS or VA). This study also develops a new paradigm for assessing the effects of physical activity on AD risk. Both interventions may be more broadly applied to other medical conditions that are prevalent in the larger VA population such as TBI and PTSD. This proposal complements existing longitudinal studies at UCLA that examine biochemical and imaging biomarkers in untreated MCI subjects relative to progressive cognitive decline. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD), a major degenerative disease of aging prevalent in the aging veteran population and reported as the 4th leading cause of death in the US, is a leading contributor to major disability, resulting in nursing home admissions and home-based care of long duration (>8 yrs). Since most rehabilitative and drug monotherapeutic strategies have failed to produce major improvements in outcome, this study focuses on early intervention of those at risk, combining a safe, novel drug therapy that directly targets multiple mechanisms precipitating memory loss. This study also challenges current paradigms for translation by controlling for a variable known to impact risk (physical activity).